Lithium as a drug

Lithium carbonate (hereinafter simply called lithium) is the most common lithium salt used as an elective drug in the treatment of bipolar disorder. Its chemical formula is Li ₂ CO ₃ .

Lithium carbonate - Chemical Structure

The stabilizing properties of lithium humor were discovered, by chance, in the 1940s by the Australian physicist John Cade. Cade hypothesized that the cause of bipolar pathologies was a toxin present in the blood and that the administration of uric acid to the patients could protect them from the toxin in question. He began to conduct experiments on rats by giving him uric acid dissolved in a lithium carbonate solution. Cade observed that the solution had a calming effect on mice and was able to establish that this effect was due to lithium and not to uric acid.

Subsequently, Cade hypothesized that lithium could be useful in the human field for the treatment of bipolar disorders and discovered that it - if given to patients regularly - not only reduced the symptoms of mania, but was able to prevent the manifestation of both the depression than of the mania itself.

Indications

For what it uses

The use of lithium is indicated for the prophylaxis and treatment of:

States of excitement in the manic and hypomanic forms;
States of depression or chronic depressive psychosis in manic-depressive psychosis.

Lithium carbonate and headache

Lithium carbonate - in addition to bipolar disorders - is also used in the second-line treatment of cluster headaches. This type of headache is characterized by intense pain located on only one side of the head.

Because of its narrow therapeutic index, lithium is used only in those patients who do not respond to any other therapy.

The dose of lithium carbonate usually used for the treatment of this pathology is 600-1500 mg of drug per day, to be taken in divided doses.

Warnings

It is important to constantly monitor the blood concentration of the lithium administered, as this drug has a narrow therapeutic index (ie a therapeutic effect ratio / restricted toxic effect). If the blood concentration is too low, the patient's symptoms will not be alleviated; if the blood concentration is too high, however, dangerous toxic effects may occur. It is recommended to start the lithium therapy with low doses and then adjust them always keeping the lithemia (concentration of lithium in the blood circulation) under control.

Before starting the lithium carbonate therapy it is good to check the cardiac, renal and thyroid function. The controls of these functions must be continued throughout the treatment period.

Regular monitoring of the blood counts of patients should be performed during lithium therapy.

Caution should be used in the administration of lithium in patients suffering from pre-existing cardiovascular pathologies and / or with a history of prolongation of the QT interval (the time required for the ventricular myocardium to depolarize and repolarize).

Lithium-based treatment should not be started in patients with kidney failure.

Lithium therapy is not recommended in patients with Addison's disease or who are in conditions associated with sodium depletion, as lithium toxicity is increased by sodium depletion. Lithium treatment is also not recommended in debilitated and / or dehydrated patients, as reduced tolerability to the drug may occur.

Particular cautions should be used when administering lithium in patients with myasthenia gravis (a neuromuscular plaque disorder), as lithium can cause an exacerbation of the disease.

Abrupt interruption of lithium treatment may increase the risk of relapse, therefore a gradual suspension is recommended under strict medical supervision.

If electroconvulsive therapy (TEC) is required, lithium intake should be discontinued at least one week before the start of the TEC.

The lithium-based therapy should be suspended 24 hours before major surgical procedures, because the reduced renal clearance (volume of plasma that the kidneys can purify in the unit of time) induced by anesthesia can lead to an accumulation of lithium. Lithium intake should then start again as soon as possible after the procedure.

Lithium carbonate can impair the ability to drive and use machines.

Interactions

The combination of lithium with antipsychotic drugs, such as haloperidol, clozapine, sulpiride and phenothiazine causes an increased risk of onset of extrapyramidal effects (Parkinson-like symptoms) and neurotoxicity. Concomitant use of lithium and such drugs should therefore be avoided. Furthermore, the simultaneous administration of lithium and some antipsychotics may mask a possible lithium poisoning, since antipsychotics can prevent the onset of nausea, which is one of the first symptoms of lithium poisoning.

Concomitant administration of lithium and sertindole, thioridazine (other antipsychotic drugs) or amiodarone (an anti-arrhythmic) increases the risk of ventricular arrhythmias.

Simultaneous administration of lithium and venlafaxine (a serotonin and norepinephrine reuptake inhibitor) may increase the serotonergic effects of lithium itself.

The combination of lithium and SSRI (selective serotonin reuptake inhibitors) may increase the risk of side effects on the central nervous system.

Concomitant administration of lithium and TCA (tricyclic antidepressants) may increase lithium toxicity.

Drugs used for the treatment of hypertension, such as methyldopa and calcium channel blockers (such as verapamil and diltiazem ) can cause an increase in lithium-induced neurotoxicity, even if the lithemia values fall within the therapeutic range.

The simultaneous administration of lithium and antiepileptic drugs (especially phenytoin, phenobarbital and carbamazepine ) may also increase the neurotoxicity of lithium.

When lithium is administered concomitantly with the following NSAIDs (non-steroidal anti-inflammatory drugs), there is a reduction in the clearance of lithium itself, with a consequent increase in lithemia and toxic effects:

Ibuprofen;
Diclofenac;
Indomethacin;
Naproxen (or Naproxen);
Ketorolac;
Mefenamic acid;
Piroxicam;
Selective COX2 inhibitors.

The association with such drugs must therefore be avoided.

Other drugs that can cause an increase in lithemia are:

ACE inhibitors, such as - for example - ramipril ;
Angiotensin II antagonists, such as - for example - valsartan, candesartan and irbesartan ;
Corticosteroids ;
Loop diuretics, such as - for example - furosemide ;
Thiazide diuretics, such as hydrochlorothiazide ;
Metronidazole, an antibiotic.

The combination with osmotic diuretics or other diuretics such as acetazolamide, amiloride and triamterene, on the other hand, can cause an increase in the elimination of lithium.

A reduction in lithemia may also occur with concomitant administration of lithium and aminophylline (an anti-asthmatic drug).

Side effects

Lithium can cause side effects, although not all patients experience them. Generally, the onset and intensity of the side effects depend on the lithemia and the different sensitivity towards the drug possessed by each individual.

The lithemia, therefore, must be monitored throughout the treatment period. However, there may be patients with lithemia levels considered toxic that do not show any sign of toxicity; other patients, on the other hand, may show signs of toxicity even with plasma concentrations of lithium considered to be therapeutic.

The following are the main side effects that can be induced by lithium.

Nervous system disorders

Lithium treatment can cause:

bench;
Epileptic attacks;
Contractions and clonic movements of the legs;
Dizziness and vertigo;
Lethargy;
Drowsiness;
Fatigue;
Confusion;
Difficulty of the word;
Amazement;
Restlessness;
Tremors;
Dry mouth;
Psychomotor delays;
Incontinence of urine and faeces;
Ataxia;
Coma.

Cardiac disorders

Lithium treatment can cause heart disease such as arrhythmias, peripheral circulation collapse and circulatory decompensation. Furthermore, it can cause prolongation of the QT interval. Cases of sudden death have also been reported.

Renal and urinary disorders

Lithium therapy can cause albuminuria (high concentration of albumin in the urine), oliguria (decreased urinary excretion), polyuria (formation and excretion of an excessive amount of urine), glycosuria (presence of sugar in the urine), glomerular and interstitial fibrosis and atrophy of the nephrons.

Endocrine disorders

Following treatment with lithium, thyroid goiter and / or hypothyroidism may occur. Rare cases of hyperthyroidism have also been reported.

Gastrointestinal disorders

Lithium can cause nausea, vomiting and diarrhea. Furthermore, it can promote the onset of anorexia.

Blood and lymphatic system disorders

The hemolymphopoietic system is that system responsible for the production of blood cells. Following the treatment with lithium, a case of alteration of this system has been reported which led to the onset of a marked leukopenia (a reduction of white blood cells in the bloodstream).

Eye disorders

Lithium treatment can give rise to transient scotomas (ie the appearance of an area of blindness - partial or complete - within the visual field) and to visual disturbances.

Skin and skin tissue disorders

After lithium therapy, drying and thinning of hair, alopecia, skin anesthesia, chronic folliculitis may occur. In addition, psoriasis patients may experience an exacerbation of psoriasis.

Metabolism and nutrition disorders

Lithium treatment could cause dehydration and weight loss.

Alteration of diagnostic tests

Lithium therapy can cause changes in the electrocardiogram (ECG) and electroencephalogram (EEG).

Overdose

If you suspect you have overdosed, you should contact a doctor immediately and contact the nearest hospital. Immediate control of lithemia is required.

Often, lithium poisoning can be the complication of long-term therapy, caused by reduced drug elimination. This reduction may depend on several factors, including dehydration, impaired renal function, infections and / or concomitant intake of diuretics or NSAIDs (see "Interaction with other drugs" section).

In case of severe poisoning the main symptoms that may arise are cardiac (ECG alterations) and neurological (vertigo, vigilance disorders and vigilant coma).

Action mechanism

The lithium ion is able to directly inhibit two signal transduction pathways, that of inositol triphosphate (through intracellular inositol depletion) and that of glycogen synthase kinase-3 (GSK-3). Indeed, it appears that both inositol and a high number of GSK-3 substrates are involved in the etiology of bipolar disorders.

Mode of Use - Posology

Lithium carbonate is available for oral administration in the form of capsules or tablets.

The lithium dosage must be established by the doctor on an individual basis according to the lithemia, the patient's tolerability and the clinical response of each individual.

Generally, it is advisable to start therapy with a low dose of medication and then adjust the dosage based on the lithemia values.

The dose of lithium usually used in adults and adolescents is 300 mg 2 to 6 times a day, given at regular intervals.

Pregnancy and breastfeeding

Lithium can cause fetal harm and is excreted in breast milk. Therefore, pregnant women - ascertained or presumed - and breastfeeding mothers should not take the drug.